Hydroxyapatite (HAp, chemical formula Ca10(PO4)6(OH)2) has attracted the attention of researchers over the past thirty years as an implant material because of its excellent biocompatibility and bioactivity. HAp has been extensively used in medicine for implant fabrication. It is commonly the material of choice for the fabrication of dense and porous bioceramics. Its general uses include biocompatible phase-reinforcement in composites, coatings on metal implants and granular fill for direct incorporation into human tissue. It has also been extensively investigated for non-medical applications such as a packing material/support for column chromatography, gas sensors and catalysts, as a host material for lasers, and as a plant growth substrate.
Previously explored methods of hydroxyapatite synthesis for particles include conventional solid-state reactions, sol-gel, phase transformation, hydrothermal, chemical precipitation, and precipitation in simulated body fluid. Solid-state reactions utilize high temperature processes (600-1250° C.) using powders of compounds such as tricalcium phosphate and calcium hydroxide. The product of the high temperature reaction is communited to a powder of a desired size range. However, materials made with this approach do not have controlled morphology. Further, they have broad size distributions and wear of the milling media and container introduces impurities. Sol-gel reactions require a sintering step to obtain crystalline product, which is not always phase-pure. A similar downfall is seen with phase transformation—the product is rarely phase-pure and does not have controllable size or morphology. Aqueous precipitation methods have been widely used, but generally either produce fiber morphologies or large agglomerates of nanostructured particles with no well-defined morphology. Simulated body fluid syntheses have not been demonstrated to make particles with controlled size and morphology and have a very low process yields, making them impractical for manufacturing.
Various morphological types of hydroxyapatite have been disclosed in patent literature. For example, U.S. Pat. No. 5,227,147 claims the production of whiskers i.e. fibers with aspect ratio above 10 for biomedical applications. The length of the whiskers according to this invention varies from 1 to 1000 microns.
A hydrothermal process for the preparation of plate-like hexagonal hydroxyapatite particles in the presence of water-miscible organic solvents is described in U.S. Pat. No. 5,427,754. The size (maximum diameter) of hydroxyapatite platelets obtained according to this invention generally falls between 50 and 200 nm.
U.S. Pat. No. 6,358,532 reveals a sol-gel method of microbead formation. The microbeads have a diameter of 0.1-6 mm and a wall thickness from 20 to 230 microns.
U.S. Pat. No. 4,335,086 describes the preparation of hydroxyapatite by heating an aqueous suspension of brushite to prepare rosette-shaped crystals. These crystals are between 40 and 70 microns in size.
Further, there are numerous patents related to production and application of spherical hydroxyapatite particles. For example, U.S. Pat. No. 5,082,566 describes a calcium-phosphate type hydroxyapatite from 0.5 to 50 microns in diameter. Hydroxyapatite is produced by spray-drying a gel or slurry form of an aqueous calcium phosphate solution into a high-temperature air stream ranging from 100-200° C. This instantaneously dries the granular apatite, which is then fired at 400-700° C.
U.S. Pat. Nos. 5,108,956 and 5,205,928 describe processes for preparing sintered microspherical hydroxyapatite particles by spray-firing a suspension of hydroxyapatite dispersed in an inflammable solvent.
The application of spherical hydroxyapatite particles of 10-100 microns in diameter as a filler for biodegradable polymers (U.S. Pat. No. 5,766,618) or an ingredient of an injectable composition (U.S. Pat. No. 5,922,025) have been speculated, but with no specific details on the production of the particles available.
Spherical hydroxyapatite aggregates (1-10 microns) built of about 0.1 micron crystals are described in U.S. Pat. No. 4,874,511 as an adsorbent for chromatograph columns. 5 mm long hydroxyapatite filaments with diameter not greater than 5 microns are disclosed in U.S. Pat. No. 5,652,056.
Spherical hydroxyapatite crystals are described in U.S. Pat. No. 6,013,591. The particles of 20-150 nm in size were sintered by pressurizing and calcination. Hollow spheres and doughnuts are disclosed in U.S. Pat. No. 5,858,318 with sizes from 1 to 8 microns.
Coatings of hydroxyapatite find use in many applications, such as, for example, biomedical devices (prosthesis, implants), protection of metal surfaces against corrosion, aggressive chemicals and environment, and strengthening of the various surfaces. The properties of hydroxyapatite depend, to a great extent, on the size and shape of the particles. Therefore, the morphology of the particles is extremely important for production of high quality coatings. However, numerous patents related to coatings are not directed to the morphology and size of hydroxyapatite particles.
U.S. Pat. No. 6,426,114 discloses a ceramic coating with a thickness of 1-5 microns made by a sol-gel method at relatively low temperature (350° C.).
U.S. Pat. No. 4,871,578 discloses the hydroxyapatite coating of metal and ceramic surfaces made by coating a substrate with tri-calcium phosphate and the subsequent transformation of this phase into hydroxyapatite by interaction with water at elevated temperature.
U.S. Pat. Nos. 4,794,023 and 4,960,646 disclose the coating of a metal substrate (titanium, titanium alloys, and stainless steel) by treatment with a nitric acid solution containing dissolved hydroxyapatite. After drying, the substrate undergoes fire treatment at 300° C., which turns the coating into hydroxyapatite. An essentially similar method is disclosed in U.S. Pat. No. 5,128,169. This patent recites metal, ceramic, and glass as possible substrates. Particles of hydroxyapatite constituting a coating have ranges from 0.1 to 1 micron.
U.S. Pat. No. 5,128,146 discloses the plasma spray coating of titanium and ceramic substrates with hydroxyapatite particles of 10 to 30 microns in diameter.
U.S. Pat. Nos. 5,164,187 and 5,279,831 disclose the solution treatment of a metal substrate that coats it with a multilayered film of hydroxyapatite made of whiskers 1-40 microns long and 0.01-20 microns in diameter. In order to control the size of hydroxyapatite crystals, these patents change the concentration of the precursor.
U.S. Pat. No. 5,609,633 recites a hydroxyapatite coating of titanium or titanium alloys in an alkaline media comprising an inner layer of amorphous titanate and an outer layer of crystalline hydroxyapatite. The thickness of the layers varies from 0.1 to 10 microns for the inner layer and above 1 micron for the outer layer.
U.S. Pat. No. 5,676,997 discloses the coating process with a precursor having salts with phosphoric acid and calcium in the presence of chelating agents, in particular, ethylenediaminetetraacetic acid with no specification of the hydroxyapatite morphology produced.
U.S. Pat. No. 5,676,997 discloses the use of ethylendiaminetetracetic acid and other chelating agents to control the synthesis of hydroxyapatite on metal substrates. According to this patent the synthesis/coating process includes the preparation of a homogeneous precursor, submerging the substrate into the precursor, and drying the precursor solution on the substrate. Thus, this method totally excludes the possibility of homogeneous nucleation of hydroxyapatite.
Degradable components as a source of phosphate are described in U.S. Pat. No. 6,426,114. The patent discloses the use of hydrolysable tri-ethyl phosphite in a sol-gel process and includes a calcination step. Another disadvantage of this method is the immiscibility of tri-ethyl phosphite with water, even in presence of organic solvents such as ethyl alcohol.
The use of water miscible tri-ethyl phosphate is described by H. K. Varma, S. N. Kalkura and R. Sivakumar in Ceramics International. 24 (1998), p. 467. The synthesis of hydroxyapatite according to this publication includes dissolution of calcium nitrate in tri-ethyl phosphate with further heating to 500° C. At this temperature, the degradation of tri-ethyl phosphate takes place with the formation of tri-calcium phosphate. Further calcination of tri-calcium phosphate leads to the formation of hydroxyapatite or a mixture of tri-calcium phosphate with hydroxyapatite. The final product has no controllable morphology and, according to XRD data, is contaminated with tri-calcium phosphate and/or calcium oxide.
Therefore, the need exists for hydroxyapatite having a controllable morphology and methods for producing the same.
Moreover, the need exist for a method of deposition of HA films over a substrate surface. Commercially, the plasma spray process (PS-HA) is the method most often used to deposit HA films on metallic implants. Films applied to the clinically relevant Ti6A14V alloy (alloyed titanium with 6 wt. % aluminum and 4 wt. % vanadium), however, lack a Ti—HA chemical intermediate bonding layer such as CaTiO3, and rely on mechanical interlock rather than chemical bonding to adhere the film to the substrate. As a result, in vivo coating delamination has been reported due to the greater interfacial strength between HA and bone, than between HA and titanium. Concerns have also been raised about the consequences of PS-HA's low crystallinity, lack of phase purity, passivation properties, and line-of-sight-limitations. In addition, plasma sprayed HA films fail to take advantage of pseudo-hexagonal HA crystallography to functionalize the film surface with the bioactive {10 1 0} crystallographic face and actively engineer protein adhesion. Molecular modeling and in vitro studies have shown that acidic bone proteins and other proteins found to bind HA with high affinity, bind to the {10 1 0} face of HA, which is prominently displayed on the six equivalent faces of the pseudo-hexagonal HA lattice21-23. HA films deposited by other techniques including sol-gel, pulsed laser deposition, magnetron sputtering, ion-beam deposition, and biomimetic crystallization share all or some of PS-HA's limitations. Therefore, there is a need to develop inexpensive reproducible HA film crystallization processes for substrates that deposit HA films with intermediate bonding layer over a substrate surface.